PROJECT SUMMARY/ABSTRACT Despite advances in pharmaceutical and surgical approaches to the treatment of Parkinson?s disease (PD), an effective disease modifying treatment remains elusive. Exercise is accepted as an adjunctive treatment to the disease; however, its disease altering properties are unclear. Data indicate that high intensity exercise has neuroprotective properties and improves motor functioning in animal models of PD. Our promising translational work in humans indicated aerobic exercise improves global motor function, upper extremity performance, and altered patterns of central nervous system activation. We recently completed a 100 person randomized clinical trial, CYClical Lower Extremity exercise for Parkinson?s trial (CYCLE Trial) (NIH R01NS673717), and results indicated an 8-week high intensity aerobic exercise program significantly improved MDS-UPDRS III scores, turning and gait speed, and information processing. The positive results persisted up to eight weeks after exercise cessation. These positive results provide strong rationale to evaluate the effectiveness of a long-term CYCLE protocol in a home-based setting in an effort to impact a greater number of individuals with PD. The primary aim of this project is to determine if long-term, high intensity aerobic exercise alters disease progression in individuals with PD. A pragmatic randomized clinical trial is proposed in which blinded clinical assessments will be coupled with biomechanical measures of motor and non-motor performance to determine the impact of high-intensity exercise on PD progression. In sum, 250 PD patients recruited from the Cleveland Clinic and University of Utah will be randomized to a high-intensity home exercise or usual and customary care (UCC) group. The CYCLE Trial protocol will be delivered to the home of the exercise group through the consumer-based Peloton Indoor Cycle, and participants will be instructed to exercise 3x/week for 12 months; the UCC group will be instructed to engage in their normal activities. The exercise and control groups will undergo identical motor and non-motor evaluation protocols at enrollment, 3, 6, 9, and 12 months. In addition to clinical measures such as the MDS-UPDRS III, systematic quantification of motor and non-motor outcomes will be collected using the PD-Performance Test (PD-PT), a validated set of biomechanical-based iPad applications created in Dr. Alberts? lab. Overall activity levels will be monitored for both groups via a wearable sensor. Combining clinical and biomechanical measures of motor and cognitive performance will accelerate the investigation and understanding of potential mechanisms underlying the positive effects of exercise on disease progression. Finally, exercise performance data including heart rate, cadence and power from each session will be gathered to monitor exercise compliance and build an exercise response predictive model. The model will facilitate a transition from general recommendation to a patient-specific exercise prescription in which potential outcomes can be estimated.